Glomerular capillary hypertension appears to play an important role in the progression of renal disease. Elevations in the mean glomerular transmembrane pressure difference (<deltaP>) are associated with the development of proteinuria and glomerular sclerosis in a variety of experimental models of progressive renal disease, and normalization of <deltaP> in rats has been shown to provide structural protection and to preserve filtration capacity and selectivity. The first aim of the proposed research is to elucidate the physical factors underlying the effects of <deltaP> on barrier function, including changes in glomerular pore-size distribution and membrane fixed charge. The second aim is to develop and verify methods for using the clearances of exogenous tracer macromolecules to estimate <deltaP>. Fractional clearances of dextran, ficoll, and dextran sulfate will be measured in normal rats and in rats with various forms of glomerular injury, following chronic or acute alterations in <deltaP>. Micropuncture measurements of glomerular hemodynamic variables in the same animals will permit the precise characterization of pressure-induced changes in membrane properties, and will allow a direct comparison with values of <deltaP> estimated using dextran sieving data. Theoretical models will be developed which provide more realistic descriptions of the dextran probes and of the glomerular barrier than are presently available. Application of these models to the micropuncture and clearance data will make it possible to assess for the first time the relative contributions of size-and-charge-related defects to the albuminuria that accompanies glomerular hypertension. Use of these models to define the optimal approach for calculating <deltaP> from dextran sieving data in rats will contribute to the long-term objective (beyond the scope of this proposal) of developing a noninvasive methodology for estimating <deltaP> in humans, for whom there is presently no method to monitor the effects of disease or therapy on <deltaP>.